Method for producing microgranulated particle

ABSTRACT

The present invention relates to a method for producing a microgranulated particle having particle size of not more than 0.2 mm, wherein a fine powder with the average particle size of not more than 10 μm, which is being agitated, tumbled or fluidized, is granulated, with a solution containing a binder alone or a binder and a surfactant being sprayed onto the surface thereof. The present invention allows to produce pharmaceutical preparations for poorly soluble and poorly absorbable drugs and preparations requiring a high content of the active ingredient. Also, it can provide an easy-to-handle powdery microgranulated particle in the field of food and fertilizers.

TECHNICAL FIELD

The present invention relates to a method for producing amicrogranulated particle. More specifically, it relates to a method forproducing a microgranulated particle, which can provide a powderymicrogranulated particle, which is suitable for pharmaceuticalpreparations of poorly soluble or poorly absorbable drugs andpharmaceutical preparations for which the content of the activeingredient should be kept high in the pharmaceutical field; and which iseasy-to-handle also in the fields of food and fertilizers.

BACKGROUND ART

Before a pharmaceutical product exerts its pharmacological effects, theactive ingredient (drug) in an oral solid pharmaceutical preparation isreleased from the preparation in the digestive tract, dissolved inhumoral fluid and absorbed into circulating blood. Poorly soluble drugs,however, may fail to satisfactorily exhibit the pharmacological effectsbecause they, because of low solubility, are sometimes excreted out ofthe body before they are completely dissolved. To date various methodshave been investigated for improving the solubility of poorly solubledrugs. For example, a poorly soluble drug is co-milled with aβ-1,4-glucan powder (Japanese Patent Examined Publication No. 53-22138),a poorly soluble drug is kneaded with a water-soluble polymeric basematerial (Japanese Patent Laid-Open No. 61-63614) and a poorly solubledrug is adsorbed to and carried by the surface of processed starch(Japanese Patent Laid-Open No. 63-101333).

It has long been known that the absorbability of orally administeredpoorly soluble drugs, in particular, depends on particle size. In suchoral preparations, the active ingredient is released afterdisintegration of the tablet, coating or capsule, and the smaller theparticle of the active ingredient is, the more rapidly the activeingredient can be dissolved and absorbed in the digestive tract afteradministration. Therefore, it is a common practice to make poorlysoluble drugs as fine as possible by pulverizing, etc. To produce such afinely milled active ingredient, however, it is necessary to use aspecial pulverizing device or to dry the active ingredient afterprecipitating it in a particularly fine form from a solvent in a specialprocess, where the wetting agent is often used in large excess.

On the other hand, an excessively fine powder has a drawback of beingdifficult in handling upon preparation, filling and packing because itshows poor fluidity and flying. It is therefore impossible to feed thepowder alone into capsules; usually, capsule-filling of the powder isfacilitated by adding a fluidizing agent as a secondary ingredient. Thiscan greatly reduce the content of an active ingredient and necessitaterelatively high-dose administration because of poor solubility and poorabsorbability. In the case of drugs to be given at high doses such asantibiotics, it is required to increase capsule size or to take somecapsules at one time, causing inconveniences to the patients upon usage.After finely powdering, pharmaceutical formulation designing bygranulation, tableting, etc. is usually conducted. Such process,however, often requires additives to obtain such properties asdisintegration of the preparation, and dissolution, dispersion andabsorption of the drug, which, in case of drugs requiring high doseadministration, can often cause inconveniences to the patients uponusage for the same reason as above.

It is, therefore, desired that the microgranulated pharmaceuticalpreparations be made with maintaining the content of the activeingredient as high as possible in order to make the above-describedproperties such as fluidity and flying optimal without sacrificing theadvantages of finely powdering such as improvements in solubility andabsorbability. However, the attempt to achieve microgranulation only bygranulation technology has limits such as a non-uniform particle sizedistribution. For example, granulation following finely powdering may beachieved by a large number of conventional granulation technologies suchas dry coating granulation using a high speed rotary mixer or anotherapparatus, solid dispersion granulation, fluidized dry granulation,spray drying granulation and wet granulation. However, all these methodsprovide granulated particles mostly having particle size of not lessthan 0.2 mm like granules and fine granules. It is technically difficultto prepare a microgranulated particle having particle size of not morethan 0.2 mm from a fine powder at high precision and high productivity.Although there are some reports on the obtainment of not more than 0.2mm fine particles by spray drying granulation or coating on fine coreparticles, it has not yet been accomplished to obtain a microgranulatedparticle from a fine powder at high precision only by granulationtechnology.

As stated above, microgranulation following finely powdering is usefulin increasing the rate of absorption of a drug to be given at a highdose. It is expected that the effects of the present art extends beyondthe pharmaceutical field because the microgranulation giving particlesize of not more than 0.2 mm can be applied also to food andfertilizers.

DISCLOSURE OF INVENTION

The present inventors intensively investigated a method for solving theabove-described problems, and found that a microgranulated particle ofnot more than 0.2 mm with good fluidity and a sharp distribution ofparticle size can be produced at high productivity by finely pulverizingsuch a compound as a poorly soluble pharmaceutically effective componenttogether with an appropriate carrier, then by repeating granulation withspraying an aqueous solution of a water-soluble polymer or such anaqueous solution further containing a surfactant as a binder in a gasstream using a means such as a jet nozzle. The inventors also found thatgranules with the same effects as above can be obtained by additionallyperforming the process of surface treatment on the surface of the finepowder by mixing and stirring smaller particles such as those of ahighly dispersible silica as a fluidizing agent before, during or aftergranulation process. The inventors made further investigations based onthese findings, and developed the present invention.

Specifically, the gist of the present invention relates to:

(1) A method for producing a microgranulated particle with particle sizeof not more than 0.2 mm, characterized by the step in which a finepowder with the average particle size of not more than 10 μm, which isbeing agitated, tumbled or fluidized, is granulated with a solutioncontaining a binder or a binder and a surfactant being sprayed onto thesurface thereof; and

(2) The microgranulated particle with particle size of not more than 0.2mm, which is produced by the method described in (1) above.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a picture showing the particle structure of the pharmaceuticalraw material (fine powder), which was observed by scanning electronmicroscopy (with 500 magnifications.)

FIG. 2 is a picture showing the particle structure of themicrogranulated particle of Example 2, which was observed by scanningelectron microscopy (with 500 magnifications.)

FIG. 3 is a picture showing the particle structure of themicrogranulated particle of Example 2, which was observed by scanningelectron microscopy (with 1500 magnifications.)

FIG. 4 is a picture showing the particle structure of themicrogranulated particle of Example 2, which was observed by scanningelectron microscopy (with 3500 magnifications.)

FIG. 5 is a picture showing the particle structure of themicrogranulated particle of Example 3, which was observed by scanningelectron microscopy (with 100 magnifications.)

FIG. 6 is a picture showing the particle structure of themicrogranulated particle of Example 3, which was observed by scanningelectron microscopy (with 500 magnifications.)

FIG. 7 is a picture showing the particle structure of themicrogranulated particle of Example 3, which was observed by scanningelectron microscopy (with 2000 magnifications.)

FIG. 8 is a graphic presentation of the particle size distributions ofthe raw material for pharmaceutical preparation (fine powder), themicrogranulated particle of Example 2 (10% granulated product) and themicrogranulated particle of Example 3 (15% granulated product).

FIG. 9 is a graphic presentation of the comparison of the area under thecurve of blood concentration (AUC) in beagles obtained afteradministration of the microgranulated particle of Example 3 and thoseobtained after administration of various controls.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present invention, a fine powder having the average particle sizeof not more than 10 μm is usually obtained by pulverizing a givencompound along with a carrier. The carrier for obtaining such a finepowder is not subject to limitation; usually, the most effective carrieris selected from the group of talc, calcium hydrogen phosphate, silicicanhydride, crystalline cellulose, lactose, mannitol, etc. As for theapparatus for pulverizing, it is useful to employ such mills as a jetmill and a hammer mill. Using such a mill, the subject compound isfinely powdered to particle size of not more than 10 μm. Some startingmaterials do not need a carrier.

Although the compound to be microgranulated in the present invention,i.e., the compound contained in the fine powder which receives thetreatment in the present invention varies depending on the field ofapplication of the present invention without limitation, it isexemplified by poorly soluble and/or poorly absorbable pharmacologicallyactive components in case of pharmaceutical application. Here, anypoorly soluble and/or poorly absorbable pharmacologically activecomponent can be used without limitation as to the degree of solubilityor absorbability, as long as its low solubility or low absorbabilitynecessitates some pharmaceutical formulation designing. Specifically,the present invention is applicable to any one of the drugs includingantibacterial agents, antiviral agents, circulatory drugs,immunoregulators, anticancer agents and anti-inflammatory agents, aslong as enhancement of its solubility or absorbability is requiredbecause of its low solubility or absorbability. The present invention isalso applicable to such fields as food and fertilizers, according tovarious purposes. In the present specification, as an example of apoorly soluble and poorly absorbable drug, an antibacterial agentreferred to as KRM-1648 is exemplified in Examples.

Success in preparing a microgranulated particle depends on how uniformlyfine droplets of a binder or those of a binder and surfactant aresprayed and coat the surface of the fine powder to bind the particleswith each other. The above-described process is facilitated by mixingand stirring particles which are smaller than the fine powder before,during or after the process in order to improve the surface condition ofthe fine powder prior to or during granulation. In this case, the binderis preferably a water-soluble polymer, with a greater preference givento a binder having a low molecular weight and low viscosity because itis weak in binding power and provides good properties formicrogranulation. In general, a water-soluble polymer increases itsviscosity and binding power to form a gel as the molecular weightincreases, causing inconveniences in handling, which in turn makes itdifficult to obtain a microgranulated particle.

The binder used in the present invention is a water-soluble polymer suchas hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodiumcarboxymethyl cellulose and polyvinylpyrrolidone. In particular, thoseof low viscosity as described above are preferred, and those whosebinding power is not too high are preferably used, since they permiteasy control of granulated particles. Examples of hydroxypropylcellulose of low viscosity include HPC-SL and HPC-SSL, both produced byNippon Soda Co., Ltd., with preference given to the grade of HPC-SSL. Asbinders, the above-mentioned water-soluble polymers may be used singlyor in combination of two or more kinds.

In the present invention, substances other than the above-describedwater-soluble polymers, such as those commonly used as binders, e.g.,starch glue, carmellose, tragacanth, gum arabic and sodium alginate, canalso be used for the above-described purpose by appropriately adjustingthe amount. The amount of such ordinary binders combinedly used isappropriately adjusted, depending on the apparatus used.

Binders having a high molecular weight are undesirable in terms of itshandling, particle properties at the time of granulation (e.g., uniformcoating on the particle surface) and other factors because theirviscosity is so high that they form a gel due to their strong bindingpower. However, as a solution to this problem, the viscosity can bereduced by the addition of a surfactant.

When a surfactant is used in combination with a binder, the surfactantis not subject to limitation, as long as its addition can lower theviscosity of binder or improve water wetting during granulation toprevent the formation of "aggregates," with a preference given tohydrophilic surfactants which can offer a greater improvement in waterwetting. Examples of preferable surfactants include hydrophilic fattyacid esters of sucrose, polyoxyl stearate, polyethylene glycol,polysorbate and polyoxyethylene polyoxypropylene glycol. Thesesurfactants exert an effect to improve the absorption of poorly solubledrug as well as the above-described effects to lower the viscosity ofbinder and control granulation.

In the present invention, a fine powder is granulated in the presence ofa binder such as a water-soluble polymer or in the presence of such abinder and a surfactant, which is combined with a surface treatmentusing particles smaller than the fine powder as a fluidizing agent toaccomplish microgranulation giving a very uniform particle sizedistribution. In the granulation which is performed in the presence of abinder like a water-soluble polymer or in the presence of such a binderand a surfactant, as stated above, to the surface of the fine powderbeing agitated, tumbled or fluidized, a water-soluble polymer alone, inthe former case, is sprayed via a nozzle, or a surfactant and awater-soluble polymer, in the latter case, are sprayed via respectivenozzles, and a mixture of the both may be sprayed. In this spraying, theamount of surfactant added is normally not more than 10% by weight ofthe fine powder, and the amount of water-soluble polymer added isnormally 1 to 20% by weight of the fine powder.

In the present invention, effective matching of the combination of afine particle, a hydrophilic surfactant and a binder with the apparatuspresumably contributes to the accomplishment of microgranulation.

For the surface treatment performed by mixing and stirring fineparticles in the present invention, particles smaller than the finepowder are used, and high speed dry mixing, for example, can be used. Inthe present invention, by mixing and stirring such fine particles, theyare made to adhere to the surface of the fine powder or made to beco-present in the vicinity of the surface. In the present invention, itis referred to as surface treatment to make the surface of the finepowder or the vicinity of the surface thereof have fine particles.

Preferable fine particles are those of a highly dispersible silica oflight silicic anhydride (Aerosil, produced by Japan Aerosil IndustryCo., Ltd.). For example, Aerosil #200 (produced by Japan AerosilIndustry Co., Ltd.) is a product of particles having the specificsurface area of 200 m² /g and the average particle size of 12 nm. Thesurface treatment with a fine particle is performed before, during orafter the granulation process. The surface treatment with a fineparticle may be conducted at any time and at any frequency withoutlimitation, before, during or after the above-described granulationprocess. For example, the surface treatment and the granulation processmay be alternatively repeated. In such case, the frequency of the repeatis appropriately chosen, depending on the kinds and amounts of the finepowder, binder, surfactant, etc., and the desired particle size of thegranulated particle. This alternative repeating method is preferablebecause it offers uniform coating and yields a heavy granulatedparticle. In the present invention, by combining the surface treatmentusing a fine particle and the granulation process, positive effects areobtained on the granulated particle itself and in improving the fluidityof the microgranulated particle obtained by the granulation. The amountof the fine particle used for this purpose is normally 1 to 5% by weightof the fine powder.

In the present invention, other components such as an absorptionpromoter and a stabilizer can also be used in the above-describedmethod. These other components are optionally chosen without limitation,depending on the compound to be granulated. For example, when thesubject compound is a water-soluble but poorly absorbable peptide, anabsorption promoter may be used concurrently. The usage of these othercomponents may be optionally determined without limitation, and they canbe added at the time of co-pulverizing the subject compound and acarrier or at the time of the surface treatment using a fine particle,or at the time of granulation in the presence of a surfactant and abinder like a water-soluble polymer.

An apparatus usable for both the process of mixing and stirring a fineparticle and the process of microgranulation in the present inventionshould have multiple functions as described below, in addition to anordinary function of fluidized bed granulation coating. An example isWurster fluidized bed granulation coaters (e.g., those produced by GlattK.K. or Powrex Corporation). This apparatus, which has a cylindricalWurster column set at the center of a container, can fluidize a finepowder or a granulated particle through the column in a single directionby an upward gas stream (jet stream), spray fine droplets of a binder orthose of a binder and a surfactant to the subject particle from the jetnozzle at the bottom for coating (bottom spray method) and performgranulation and drying.

In addition to the above-described apparatus, multi-function combinedgranulation coaters of the agitating tumbling fluidized bed type (e.g.,SPIR-A-FLOW granulation coater, produced by Freund Industrial Co., Ltd.,and New-Marumerizer, produced by Fuji Paudal Co., Ltd.), multi-functioncombined granulation coaters of the tumbling fluidized bed type (e.g.,Multiplex, produced by Powrex Corporation) and other apparatuses canalso be used. Spraying methods of these multi-function combinedgranulation coaters include the top spraying method, in which dropletsare sprayed from the top, the middle spraying (tangential spraying)method, in which droplets are sprayed from a side of the bottom, and thebottom spraying method. However, the middle spraying (tangentialspraying) method or the bottom spraying method is effective formicrogranulation in many cases. In short, it is necessary to control thegranulation to yield a microgranulated particle by binding togetheruniformly coated particles, which can be accomplished by preventingflocking (aggregation) of the subject particles during the granulationprocess by minimizing the diameter of the droplets of a binder and asurfactant and increasing the speed at which the droplets collide withthe fine powder or granulated particle during spraying and granulation.Such apparatus with multiple functions is exemplified by the one usingone of the above-described spraying methods. The concentration/amount ofthe fine particle, hydrophilic surfactant, binder, etc. used for suchsurface treatment and granulation are optionally chosen according to theapparatus used so that the granulated particle has desired particle sizeof not more than 0.2 mm. The particle size mentioned here is themeasurements obtained by scanning electron microscopy or by sieving.

The granulated particle thus obtained has particle size of not more than0.2 mm, preferably not more than 0.1 mm, very sharp particle sizedistribution, improved fluidity and improved water wetting. Thegranulated particle of the present invention is also useful as a dosageform for pharmaceutical preparations requiring high dose administrationbecause they have a high content of the active ingredient because ofexcipient-free granulation. Also, improvement in absorption can beexpected. Usually, the obtained granulated particle contains a finepowder at not less than 80% and an active ingredient at not less than60%, preferably not less than 70%. Of course, this granulated particlecan be tableted by ordinary methods. They are also applicable to suchfields as food and fertilizers as well as pharmaceuticals.

The present invention is hereinafter described in more detail by meansof the following working examples and test examples, but the inventionis not limited by these examples.

In the examples of the present invention, KRM-1648 (C₅₁ H₆₄ N₄ O₁₃,M.W.=941.09), a drug under research and development by KanegafuchiKagaku Kogyo K.K., was used as a poorly soluble and poorly absorbabledrug model. KRM-1648 is a poorly soluble antibacterial substance whichhardly dissolves in water. Because it has a dark purple color,particularly when it is finely powdered, poses problems in handlingduring preparation as described above, including contamination andflying. KRM-1648 is an abbreviation for3'-hydroxy-5'-[4-isobutyl-1-piperazinyl]benzoxazinorifamycin, aderivative of rifamycin S, exhibiting strong antibacterial actionagainst infectious atypical acid-fast bacteria such as Mycobacteriumavium complex and Mycobacterium tuberculosis to prevent opportunisticinfection in persons with immunological depression. ##STR1##

EXAMPLE 1

Crystalline KRM-1648 having the average particle size of about 20 to 40μm, mixed with JP D-mannitol (produced by Kao Corporation) as a carrierin a 4:1 ratio by weight, was twice pulverized using a hammer mill(Sample Mill KIIW-1, produced by Fuji Paudal Co., Ltd.) to yield a finepowder of not more than 10 μm in the average particle size, which wasused as a starting material for preparation. 250 g of this fine powderand 5 g of Aerosil #200 (produced by Japan Aerosil Industry Co., Ltd.)were placed in a Wurster fluidized bed granulation coater (Glatt GPCG-1Wurster, produced by Glatt K.K.) and stirred and mixed at a high speedin the fluidized bed chamber so that the Aerosil #200 adheres to thesurface of the starting material powder for surface treatment. Then, anaqueous mixture solution containing 0.05% of DK Ester F-160 (produced byDai-ichi Kogyo Seiyaku Co., Ltd.), a fatty acid ester of sucrose, and 5%of HPC-SSL (produced by Nippon Soda Co., Ltd.), a water-soluble polymerhydroxypropyl cellulose, was sprayed in the form of gas stream via a jetnozzle using a bottom spray for granulation. When granulation withspraying was carried out until the ratio of HPC-SSL to the activeingredient, KRM-1648, became 5%, spraying was stopped, and 4 g of theabove-described Aerosil #200 was added, and the particle was subjectedto surface treatment in the drying process by high speed fluidizedstirring and mixing within the same apparatus, to yield a fine andhalf-granulated particle having particle size of not more than about 20μm as determined by scanning electron microscopy.

EXAMPLE 3

The fine and half-granulated particle obtained in Example 1 was placedin a Wurster fluidized bed granulation coater (Glatt GPCG-1 Wurster,produced by Glatt K.K.), and then the above-described aqueous solutioncontaining 0.05% of DK Ester F-160 (produced by Dai-ichi Kogyo SeiyakuCo., Ltd.), a fatty acid ester of sucrose, and 5% of HPC-SSL (producedby Nippon Soda Co., Ltd.,) a water-soluble polymer hydroxypropylcellulose, was sprayed in the form of gas stream via a jet nozzle duringgranulation until the ratio of HPC-SSL to the active ingredient KRM-1648became 10%. Then, in the drying process, 2 g of Aerosil #200 (producedby Japan Aerosil Industry Co., Ltd.) was added, and the particle wassubjected to surface treatment by high speed fluidized stirring andmixing in the same apparatus to yield a microgranulated particle(particle size of 20 to 40 μm as determined by scanning electronmicroscopy.) The contents of the fine powder and KRM-1648 in thegranulated particle were 87% and 70%, respectively.

EXAMPLE 3

The microgranulated particle obtained in Example 2 was placed in aWurster fluidized bed granulation coater (Glatt GPCG-1 Wurster, producedby Glatt K.K.), and then the above-described aqueous solution containing0.05% of DK Ester F-160 (produced by Dai-ichi Kogyo Seiyaku Co., Ltd.),a fatty acid ester of sucrose, and 5% of HPC-SSL (produced by NipponSoda Co., Ltd.), a water-soluble polymer hydroxypropyl cellulose, wassprayed in the form of gas stream via a jet nozzle during granulationuntil the ratio of HPC-SSL to the active ingredient KRM-1648 became 15%.Then, in the drying process, 4 g of Aerosil #200 (produced by JapanAerosil Industry Co., Ltd.) was added, and the particle was subjected tosurface treatment by high speed fluidized stirring and mixing in thesame apparatus to yield a microgranulated particle (particle size of 50to 70 μm as determined by scanning electron microscopy.) The contents ofthe fine powder and KRM-1648 in the granulated particle were 82% and66%, respectively.

EXAMPLE 4

Crystalline KRM-1648 having the average particle size of about 20 to 40μm, mixed with JP D-mannitol (produced by Kao Corporation) as a carrierin a 4:1 ratio by weight, was twice milled using a hammer mill (SampleMill KIIW-1, produced by Fuji Paudal Co., Ltd.) to yield a fine powderof not more than 10 μm in average particle size, which was used as astarting material for pharmaceutical preparation. 800 g of this finelypowdered starting material and 16 g of Aerosil #200 (produced by JapanAerosil Industry Co., Ltd.) were placed in a SPIR-A-FLOW agitating andtumbling fluidized bed granulation coater (produced by Freund IndustrialCo., Ltd., SFC-MINI), and stirred and mixed at a high speed in thefluidized bed chamber to give surface treatment with the Aerosil #200 tothe surface of the starting material powder. Then, an aqueous solutioncontaining 0.05% of DK Ester F-160 (produced by Dai-ichi Kogyo SeiyakuCo., Ltd.), a fatty acid ester of sucrose, and 5% of HPC-SSL (producedby Nippon Soda Co., Ltd.), a water-soluble polymer hydroxypropylcellulose, was sprayed in the form of gas stream via a jet nozzle forgranulation. During spraying, the bottom plate is rotating and thepowder is agitated and tumbled in the bottom. The above-mentioned middlespraying method (tangential spraying) allows the spraying of thesolution to be directed toward the center of the powder.

The spraying was stopped when the granulation proceeded to the stepwhere the ratio of HPC-SSL to the active ingredient KRM-1648 became12.5%; 16 g of the above-described Aerosil #200 was added; and theparticle was subjected to surface treatment in the drying process byhigh speed fluidized stirring and mixing within the same apparatus toyield a microgranulated particle. To make sure, a 150-mesh sieve wasused and a microgranulated particle with particle size of not more thanabout 0.1 mm was obtained in an 80% yield. The contents of the finepowder and KRM-1648 were 86% and 69%, respectively.

Test Example 1

The finely powdered starting material for pharmaceutical preparationobtained by pulverizing, and the microgranulated particles obtained inExamples 2 and 3 were observed by SEM scanning electron microscopy. Theapparatus used was of HITACHI S 430 type. The microscopic photo (x 500)of the starting material (fine powder) is given in FIG. 1; those (x 500,x 1500 and x 3500) of the microgranulated particle of Example 2(hereinafter abbreviated as 10% granulated particle), in FIGS. 2 to 4;and those (x 100, x 500 and x 2000) of the microgranulated particle ofExample 3 (hereinafter abbreviated as 15% granulated particle), in FIGS.5 to 7. As obvious from FIGS. 1 to 7, the particle sizes were about 5 to10 μm for the starting material, about 20 to 40 μm for themicrogranulated particle of Example 2, and about 50 to 70 μm for themicrogranulated particle of Example 3.

To accurately grasp the particle size, a volume analysis of the particlesize distribution was conducted by image processing after photographing.FIG. 8 shows the results on the particle size distribution based on theparticle volume by size. The apparatus used was an image analyzer PIASIII, produced by PIAS Company. As obvious form FIG. 8, it is suggestedthat the method of the present invention offers a microgranulatedparticle having particle size of not more than 0.2 mm with the averagebetween 70 and 80 μm and very sharp particle size distribution.

Test Example 2

The finely powdered starting material obtained by pulverizing and themicrogranulated particles obtained in Examples 1 through 3 were measuredfor the angle of repose, an index of fluidity, using a repose anglemeter (produced by Konishi Iryoki K.K.). The results, given in Table 1,suggest the fluidity of the granules of the present invention isimproved.

                  TABLE 1                                                         ______________________________________                                        Samples            Angle of repose                                            ______________________________________                                        Starting material  not less than 55°                                   (fine powder)                                                                 Microgranulated particle of                                                                      "                                                          Example 1                                                                     Microgranulated particle of                                                                      43°                                                 Example 2                                                                     Microgranulated particle of                                                                      37°                                                 Example 3                                                                     ______________________________________                                    

Test Example 3

To evaluate the absorbability of microgranulated particle (15%granulated particle) obtained in Example 3, the particle was encapsuledin a hard capsule and orally administered to 4 male beagle dogs weighingabout 10 kg at a dose of 50 mg KRM-1648/animal. At 1, 3, 5, 8, 12 and 24hours following administration, the blood concentration was measured byHPLC to obtain the area under the blood concentration curve (AUC). Forcontrol, crystalline KRM-1648 before co-pulverizing and a powderobtained by pulverizing the crystal with a mortar, were each encapsuledin hard capsules. These hard capsules, and a suspension of themortar-milled crystal in 2.5% gum arabic, were each orally administeredin the same manner as above, and each AUC was obtained in the samemanner for comparison. As obvious from FIG. 9, it was shown that thegranulated particle of the present invention have remarkably improvedabsorbability.

INDUSTRIAL APPLICABILITY

The present invention provides a method for producing a microgranulatedparticle having markedly uniform particle size of not more than 0.2 mmfrom a fine powder, which, in the field of pharmaceuticals, allows toproduce pharmaceutical preparations of poorly soluble and poorlyabsorbable drugs and those requiring a high content of the activeingredient. It can provide easy-to-handle materials also in the fieldsof food and fertilizers.

What is claimed is:
 1. A method for producing microgranulated particles,which comprises granulating a fine powder with an average particle sizeof not more than 10 μm into microgranulated particles having a particlesize of not more than 0.2 mm, wherein said fine powder is beingagitated, tumbled or fluidized, while spraying a solution containing abinder or a binder and a surfactant onto a surface of the fine powder tocoat the fine powder with the binder or the binder and the surfactant.2. The production method according to claim 1, further comprising inadvance of the granulating step, the step of mixing and stirring thefine powder with fine particles having a particle size smaller than thefine powder particle size.
 3. The production method according to claim1, further comprising during and/or after the granulating step, the stepof mixing and stirring the fine powder with fine particles having aparticle size smaller than the fine powder particle size.
 4. Theproduction method according to claim 2, wherein the fine particle is ahighly dispersible silica of light silicic anhydride.
 5. The productionmethod according to claim 3, wherein the step of mixing and stirring thefine particles and the step of granulating are alternately repeated. 6.The production method according to claim 1, wherein the binder is alow-viscous binder comprising one or more kinds of water-solublepolymers selected from the group consisting of hydroxypropyl cellulose,hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose andpolyvinylpyrrolidone.
 7. The production method according to claim 1,wherein the surfactant comprises one or more kinds of hydrophilicsurfactants selected from the group consisting of hydrophilic fatty acidesters of sucrose, polyoxyl stearate, polyethylene glycol, polysorbateand polyoxyethylene polyoxypropylene glycol.
 8. The production methodaccording to claim 1, wherein the fine powder comprises a poorly solubleand/or poorly absorbable pharmacologically active ingredient.
 9. Theproduction method according to claim 8, wherein the poorly solubleand/or poorly absorbable pharmacologically active ingredient is anantibacterial agent3'-hydroxy-5'-(4-isobutyl-1-piperazinyl)-benzoxazinorifamycin.
 10. Theproduction method according to claim 1, wherein the content of the finepowder in the granulated particle is not less than 80%.
 11. Theproduction method according to claim 1, wherein the granulating step isconducted by using a Wurster fluidized bed granulation coater, or amulti-function combined granulation coater of the agitating and tumblingfluidized bed type or of the tumbling fluidized bed type.
 12. Amicrogranulated particle with particle size of not more than 0.2 mmproduced by the method according to claim
 1. 13. A pharmaceuticalpreparation comprising the granulated particle of claim 12, wherein thepoorly soluble and/or poorly absorbable pharmaceutically activeingredient is the antibacterial agent3'-hydroxy-5'-(4-isobutyl-1-piperazinyl)-benzoxazinorifamycin.
 14. Theproduction method according to claim 1, wherein the microgranulatedparticles have a particle size of not more than 0.1 mm.